Non-alcoholic fatty liver disease (NAFLD) is a clinical-pathological condition with a wide spectrum of histologic abnormalities and clinical outcomes. While hepatic steatosis alone is a benign condition, non- alcohol steatohepatatis (NASH) is the most serious form of NAFLD and is characterized by the histologic findings of alcoholic hepatitis occurring in patients who deny significant alcohol intake. The prevalence of NASH is estimated to be 3% in the general population and up to 20% in patients with type II diabetes and obesity; thereby making NASH the most common form of chronic liver disease in the United States. Over a 10-year period cirrhosis develops in 25% of NASH patients with a liver related mortality of 10%. The pathogenesis of NASH has been proposed to occur in two steps. The first step involves insulin resistance, which causes hepatic seatosis. The second sep involves lipid-laden hepatocytes that serve as a substrate for oxidative stress, which via lipid peroxidation and inflammatory cytokines, results in fibrosis and hepatocyte necrosis. Short duration and small sample size of previous NASH clinical trials have limited these trials from obtaining valid end points. Consequently the therapy of NASH remains uncertain. Therefore, the overall objective of this grant is twofold. The first is to create an infrastructure for patient recruitment and retention in large multi-center trials using carefully defined and uniform criteria for the diagnosis of NASH. The second is to evaluate different therapies directed at both pathogenic steps in NAS. A show-term (6-month) trial will attempt to improve insulin sensitivity by decreasing visceral fat with diet alone or diet plus exercise. In a long-term (3-year) trial, two different doses of vitamin E will be used to reduce oxidative stress and decrease fibrosis. Although both studies could not performed as independent trials, it is anticipated that by performing these trials in series and treating both pathogenetic steps (as proposed), an optimal therapeutic response will be obtained.